Pneumocystis (PC) pneumonia continues to be a leading cause of opportunistic infections in patients living with HIV. Though we are thirty years into the HIV epidemic very little is known about the lifestyle of the PC organism and how it interacts with the immune system. The field is hampered by the inability to culture the organisms for more than a couple weeks and the problem of separating the two identifiable life forms, the ascus and trophic forms, resulting in a paucity of information regarding how these separate life forms interact with the host and the immune response. Recently ?-glucan synthesis inhibitors (a class of drugs called echinocandins) have been used to eliminate the ascus form of the organisms in vivo giving us the ability to obtain a purified population of trophic forms and to examine trophic form interactions with host immune cells. Our preliminary data demonstrates that trophic forms of PC inhibit TNF production of alveolar macrophages after stimulation by lipopolysaccharide (LPS), ?- glucans, or lipoteichoic acid (LTA) in vitro. Additionally, in vivo we found that trophic forms inhibit TNF production in the lungs of mice challenged with a small dose of LPS. We hypothesize that the trophic forms of PC act to temper the inflammatory response to ?-glucans in the ascus forms of PC. The goal of this proposal is to determine the significance and mechanism of the inhibitory activity of trophic forms of PC. We propose two aims to address our hypothesis. In aim 1 we will determine whether trophic forms of PC alter the balance of inflammation induced by ?-glucan in vivo. In aim 2 we will determine whether trophic forms of PC dampen inflammation induced by innate immune responses and identify pattern recognition receptors on macrophages that interact with tropic forms of PC.